The neurohumoral systems and kidneys are closely linked in long-term control of cardiovascular dynamics. Our previous studies have suggested that abnormal kidney function, manifested by impaired pressure natriuresis, plays a key role in all forms of chronic hypertension studied thus far. Some abnormalities of pressure natriuresis originate intrarenally, but many occur through activation of neurohumoral mechanisms that impair renal excretory capability. For this reason, a major part of our research program has been directed toward understanding the neurohumoral and intrarenal mechanisms that regulate kidney function, and how these are altered in chronic hypertension. During the previous project period, we investigated the mechanisms of obesity hypertension, which has special relevance to human essential hypertension. Our studies indicate that activation of the sympathetic nervous system (SNS), via the renal nerves, plays a major role in the pathophysiology of obesity-hypertension. The proposed studies will examine novel mechanisms that may contribute to activation of the SNS and hypertension as well as regulation of food intake and metabolism in obesity. The central hypothesis of this proposal is that excess adiposity increases circulating leptin which acts on the hypothalamus to stimulate the proopiomelanocortin (POMC) pathway and melanocortin 3/4-receptors (MC3/4-R) which, in turn, causes increased renal SNS activity, impaired pressure natriuresis, and hypertension. We will use chronically instrumented rats, MC4-R knockout mice, and chronically instrumented obese dogs in these studies since each species has certain advantages in testing the overall hypothesis. Chronically instrumented rats will be used in conjunction with specific pharmacological agonists of the MC3/4-R to test the hypothesis that chronic activation of the MC3/4-R raises arterial pressure via increased renal SNS activity. We will also use specific antagonists of the MC3/4-R to test the hypothesis that hyperleptinemia increases arterial pressure by activating the MC3/4-R, and that chronic blockade of the MC3/4-R causes obesity but little or no impairment of pressure natriuresis or increased arterial pressure. The MC4-R knockout mouse model will be used to provide a non-pharmacologic means of testing whether the absence of a functional MC4-R attenuates or abolishes the chronic effects of obesity or hyperleptinemia to raise arterial pressure. The obese dog model will be used to test the hypothesis that a functional hypothalamic MC3/4-R is necessary for dietary-induced obesity to increase SNS activity, impair pressure natriuresis, and raise arterial pressure since this model closely mimics obesity-hypertension in humans. This model also permits extensive investigation of the hemodynamic, renal, endocrine, and metabolic mechanisms that mediate increased blood pressure during the development of obesity or changes in activity of the leptin-POMC pathways. The use of multiple species not only permits us to effectively test the overall hypothesis, but also provides a greater assurance that our results have broad applicability.